Over the past decade there has been growing appreciation of mental disorders as brain circuit disorders that are influenced by genetic and environmental factors. This application is being submitted in response to RFA- MH-12-100, which stems from the NIMH Research Domain Criteria (RDoC) project that aims to further the long-range goal of developing a diagnostic system for mental disorders informed by genetics, neuroscience, and psychology. This application focuses on the RDoC domain Negative Valence Systems, or more specifically, acute threat, fear. The proposed investigation utilizes a translational neuroscience perspective to study 400 10-15 year old children: 200 community-control and 200 maltreated children who are at-risk of developing trauma-related psychiatric problems (e.g., depression, anxiety, substance misuse). Assessments of other relevant RDoC domains and constructs are also planned. Maltreated children will be recruited for the present study within six months of out-of-home placement (e.g., foster care) due to a substantiated report of abuse or neglect of sufficient severity to warrant removal. Consistent with the RDoC matrix, multiple units of analyses will be examined in the proposed investigation: genes, circuits, and self-reports of clinical symptoms. Specifically, we will examine: epigenetic modifications in genes involved in fear conditioning, synaptic plasticity, and myelination/circuitry formation; multiple indices of white matter structure and function; task-activated and resting-state fear circuitry measures; and dimensional assessments of trauma-related symptomatology. Comprehensive trauma history and social supports measures will also be collected. DNA and clinical assessments will be collected on the full cohort of 400 children; the comprehensive imaging protocol will only be completed on 125 youth. The proposed study of maltreated children has a number of advantages for the RDoC project, including: the study of a subset of patients that are frequently treatment resistant to standard clinical interventions; examination of a relatively homogenous sample with the onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established relevant animal models to facilitate translational research. In addition, the study of this cohort close to the time of abuse and removal from parental care significantly enhances power to detect epigenetic changes associated with risk and resilience. It is hoped that this research program organized around the acute threat, fear circuit, a primary circuit affected in traumatized individuals, will accelerate knowledge regarding how early childhood trauma influences the entire range of analysis from genes to behavior. The research team for this project is comprised of basic and clinical scientists with expertise in psychiatric and other health (e.g., cancer) areas, facilitating synerg and cross-fertilization of research efforts to further the goals of the RDoC project and this study of risk and resilience in maltreated children. ! PUBLIC HEALTH RELEVANCE: This investigation represents a study within a study; one that will provide rich data for the RDoC project; and one that will also provide invaluable data on risk and resilience in maltreated children. This application delineates plans to examine the RDoC domain Negative Valence Systems, or more specifically, acute threat - fear; and proposes to collect data on multiple units of analysis included in the RDoC matrix: genes, circuits, and self-reports of clinical symptoms. !